The pyrrolo[2,1-c][1,4]benzodiazepines are a family of DNA interactive antitumour antibiotics derived from Streptomyces species. Examples of naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines include anthramycin, tomaymycin, sibiromycin and DC-81. These compounds show their biological activity through covalent binding via their N10-C11 imine/carbinol amine moiety to the C2-amine position of a guanine residue within the minor groove of DNA giving rise to the preference for Pu-G-Pu sequences. (Kunimoto, S.; Masuda, T.; Kanbayashi, N.; Hamada, M.; Naganawa, H.; Miyamoto, M.; Takeuchi, T and Unezawa, H. J. Antibiot., 1980, 33, 665.; Kohn, K. W. and Speous, C. L. J. Mol. Biol., 1970, 91, 551.; Hurley, L. H.; Gairpla, C. and Zmijewski, M. Biochem. Biophy. Acta., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H. Biochemistry, 1981, 20, 7572.) The molecules have a right-handed twist, when viewed from the C-ring towards the A-ring. This enables the PBD to mirror the curvature of B-form DNA and maintain isohelical contact with the walls and floor of the minor groove.
In the last few years a growing interest has been shown in the development of new pyrrolo[2,1-c][1,4]benzodiazepine hybrids. Many PBD conjugates have been synthesized and investigated for their anticancer activity (Thurston, D. E.; Morris, S. J.; Hartley, J. A. Chem. Commun. 1996, 563.; Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org. Chem. 1999, 64, 290.; Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K.; Ramesh, G Bioorg. Med. Chem. Lett. 2002, 12,1933, Kamal, A.; Reddy, B. S. N.; Reddy Indian patent application No.209/DEL/2000). Recently C-8 linked PBD dimers with C2/C2 exo-unsaturation have been designed and synthesized (Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, N. A.; Adam, L. J.; Jenkins, T. C.; Kelland, L. R. and Thurston, D. E., J. Med. Chem. 2001, 44, 737). Also, non cross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumor activity (Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M. J. Med. Chem. 2002, 45, 4679).
During earlier studies in this laboratory anthraquinone has been linked through its amino functionality to the C8 position of the A-ring of PBDs which have shown promising anticancer activity (Kamal, A.; Ramu, R.; Khanna, G. B. R.; Bioorg. Med. Chem. Lett. 2004, 14, 4907, Kamal, A.; Ramu, R.; Khanna, G. B. R. PCT Patent Appl. No. PCT/IN04/00212, U.S. patent application Ser. No.11/024,240).
However, in the present invention the two pbd units have been joined to the 1,4-positions of the anthraquinone through their a-c8 positions via alkanediyldioxy bridge with linkers of varying lengths provide novel pyrrolo[2,1 -c][1,4]benzodiazepines useful as anticancer agents. It also provides a process for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepines useful as antitumor agents.
